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F.D.A. Panel Urges Stronger Warning on Antidepressants

BETHESDA, Md., Sept. 14 - Federal drug regulators should warn physicians and patients in the strongest possible terms that antidepressants not only cause some children and teenagers to become suicidal but most have also failed to cure their depression, a federal advisory committee voted Tuesday.

The committee voted 15 to 8 that the Food and Drug Administration should mandate that the drugs contain "black box" warnings on the sheet of information that physicians review when prescribing drugs. This type of warning is in boldface type, surrounded by a black border and placed at the top of a drug's warning label.

"A black box is the strongest emphasis on warning information that we know how to do," said Dr. Robert Temple, director of the agency's office of medical policy.

After two days of testimony about the risks and benefits of the pills, the committee also agreed unanimously that the agency should require pharmaceutical manufacturers to attach a patient guide to the drugs' packaging that would describe the risks of suicide in plain language. Hundreds of approved drugs have black-box warnings, but fewer than 30 are required to have such patient attachments, F.D.A. officials said.

Children and teenagers who take antidepressants are twice as likely as those given placebos to become suicidal, according to studies presented to the committee. Still, the overall risk of suicide is low. If 100 patients are given the drugs, 2 or 3 more will become suicidal than would have had they been given placebos.

The agency is not required to follow the advice of its advisory committees, but it usually does. The committee could have recommended banning the use of antidepressants by children and teenagers, as British regulators did in December. But no one on the committee strongly advocated such a step and even critics of the drugs seemed torn about whether such action was needed.

The suicide risk, however small, appeared to concern some committee members, mainly because the benefits of the medications are unclear at best. Most of the drugs failed in studies to ameliorate the symptoms of depression in teenagers and children. One large study found that Prozac was effective in youngsters but not by much. And with little benefit to recommend the medicines, some committee members said that any risk was all but unacceptable.

"We have very good evidence of harm and very little evidence of efficacy," said Dr. Thomas Newman, a professor of epidemiology and pediatrics at the University of California, San Francisco. "It would not be that bad if the use of these drugs declined, because it's very unclear that they work."

Even after months of controversy about the links between antidepressants and suicide, such a decline has yet to materialize. In 2002, the last year for which total figures are available, doctors wrote nearly 11 million prescriptions for the pills to teenagers and children. That represented almost 8 percent of all antidepressant prescriptions.

After the F.D.A. mandated in March that manufacturers state on drug prescription sheets that they may be linked to suicide, prescriptions of the drugs for youngsters continued to climb by nearly 8 percent, the committee was told.

Some committee members said that such prescribing habits have been driven by advertising. Pfizer, for instance, spends millions of dollars advertising Zoloft, its huge-selling antidepressant.

If the F.D.A. follows the committee's recommendation by mandating a black-box warning, however, Pfizer's advertisements, which feature a cartoon head in obvious distress, will have to mention the risk of suicide.

Susan Bro, a Pfizer spokeswoman, said that it was too early to speculate on how such a requirement might affect the company's advertising. Ms. Bro said that Pfizer shared "the F.D.A.'s concern for this vulnerable patient population and for the devastating impact of untreated depression."

Pfizer failed in two tests to prove that Zoloft effectively treats depressed teenagers and children, but doctors prescribe Zoloft to youngsters more often than any other antidepressant.

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Committee members pushed for the patient attachment after hearing dozens of bereaved relatives describe physicians who they said had cavalierly prescribed antidepressants to children for a whole range of conditions that the drugs were never intended to treat and then failed to warn patients about the risks.

"If I heard nothing else from the public, it was that they want to be warned," said Jean Bronstein, a nurse from Sunnyvale, Calif., who serves as a consumer representative to the advisory committee.

Advocates who have argued for years that antidepressants are over-used and often dangerous said that they were pleased with the committee's recommendations.

"That they voted for a black box is more than I ever would have hoped for," said Sara Bostock, 58, of Atherton, Calif. Ms. Bostock's 25-year-old daughter, Cecily, stabbed herself in the throat after being prescribed an antidepressant.

The members of the committee who opposed the addition of black-box warnings to the drugs' physician-information sheet said they did so because they feared such warnings would discourage physicians from treating depressed youngsters.

Dr. Matthew V. Rudorfer, a panel member from the National Institute of Mental Health, said that 15 percent of teenagers with untreated depression commit suicide -- a much greater risk than that presented by the drugs themselves, he said. And another panelist from the institute, Dr. Daniel Pine, noted that one-on-one talk therapy has been found in a landmark study to work no better in treating depression in teenagers and children than placebos. In that study, published this summer, Prozac was more effective by some measures than either talk therapy or placebos.

To some, such results, however meager, mean that these drugs can help. But others point out that most other studies, many of them smaller, have shown that the drugs do not work.

In comments after the hearing, Dr. Temple of the F.D.A. said he hoped that the committee's decision would help dim the controversy that has swirled around the agency for much of the year.

The agency held a similar hearing in February in which top agency officials treated with skepticism findings from numerous clinical trials that the drugs may lead some patients to become acutely suicidal.

Weeks after the hearing, leaked documents showed that a top safety reviewer at the agency, Dr. Andrew Mosholder, had concluded that the drugs did cause some patients to become suicidal and that the drugs' risks outweighed their benefits in children and teenagers. Top officials were forced to admit that Dr. Mosholder's testimony at the February meeting was canceled because of his views.

Senate and House committees initiated investigations. More leaks ensued. Agency officials insisted that they simply needed time to undertake a more thorough review of the studies. That review was completed last month with conclusions nearly identical to Dr. Mosholder's original analysis.

In comments after the meeting, Dr. Temple said that the agency, which has already said it will consider label changes for antidepressants, said it would decide on those changes within a few months.

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A version of this article appears in print on September 15, 2004, on Page A00001 of the National edition with the headline: F.D.A. Panel Urges Stronger Warning On Antidepressants. Order Reprints|Today's Paper|Subscribe